Facile synthetic pathway for nicotinonitriles 5a‒o, 7a‒i was demonstrated through reaction of ketones 4a‒k, 6a‒f with ylidenemalononitrile 3 in the presence of sodium alkoxide. Meanwhile, nucleophilic attack of amines on 2-bromonicotinonitrile 9 (obtained through reaction of propenone 8 with malononitrile, followed by bromination with bromine in acetic acid) afforded 3-pyridinecarbonitriles 11a‒d. Single crystal X-ray of compound 7i reveals the monoclinic space group C2/c with 8 molecules per unit cell. Optimized structure of 7i [DFT/B3LYP, 6-31G(d,p)] shows close correlations to that of X-ray study. Compound 5l seems superior among all the synthesized analogues exhibiting bronchodilation properties about three folds potency compared to theophylline (standard reference) through pre-contracted tracheal rings with histamine standard method. Also compound 5a reveals promising observations (about two folds potency of the standard reference). Molecular modeling studies (3D-pharmacophore and 2D-QSAR) supported the observed biological properties.
Keywords: Bronchodilation; Nicotinonitrile; Pharmacophore; QSAR.
Copyright © 2017 Elsevier Masson SAS. All rights reserved.